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• W2023243872 abstract "Epithelial–mesenchymal transition represents a key event in cancer progression and has emerged as a promising anticancer target. Estrogen-related receptor alpha (ERRα) is frequently elevated in advanced-stage ovarian cancer, but its potential role in tumor progression is not known. Here we show that ERRα functions in epithelial–mesenchymal transition and in subsequent stem cell traits responsible for the acquisition of high degree of aggressiveness and potential for metastasis that are characteristic of ovarian cancer. Importantly, targeted inhibition of ERRα also inhibited the expression of Snail, a repressor of E-cadherin and an inducer of epithelial–mesenchymal transition. Interestingly, induction of Snail resulted from not only changes in mRNA transcription rate but also mRNA stability. We thus identified the miR-200 family as a new player in the ERRα-mediated posttranscriptional regulation of Snail, and antagonism of miR-200a/b could revert the decreased expression of Snail and reversal of epithelial–mesenchymal transition and stem cell characteristics due to ERRα depletion. Finally, we showed that RNA interference–mediated inhibition of ERRα significantly reduced tumor burden, ascites formation, and metastatic peritoneal nodules in vivo in an orthotopic model of ovarian cancer. These results suggest ERRα activation as a mechanism of tumor aggressiveness and imply that targeting ERRα may be a promising approach in ovarian cancer treatment. Epithelial–mesenchymal transition represents a key event in cancer progression and has emerged as a promising anticancer target. Estrogen-related receptor alpha (ERRα) is frequently elevated in advanced-stage ovarian cancer, but its potential role in tumor progression is not known. Here we show that ERRα functions in epithelial–mesenchymal transition and in subsequent stem cell traits responsible for the acquisition of high degree of aggressiveness and potential for metastasis that are characteristic of ovarian cancer. Importantly, targeted inhibition of ERRα also inhibited the expression of Snail, a repressor of E-cadherin and an inducer of epithelial–mesenchymal transition. Interestingly, induction of Snail resulted from not only changes in mRNA transcription rate but also mRNA stability. We thus identified the miR-200 family as a new player in the ERRα-mediated posttranscriptional regulation of Snail, and antagonism of miR-200a/b could revert the decreased expression of Snail and reversal of epithelial–mesenchymal transition and stem cell characteristics due to ERRα depletion. Finally, we showed that RNA interference–mediated inhibition of ERRα significantly reduced tumor burden, ascites formation, and metastatic peritoneal nodules in vivo in an orthotopic model of ovarian cancer. These results suggest ERRα activation as a mechanism of tumor aggressiveness and imply that targeting ERRα may be a promising approach in ovarian cancer treatment. Ovarian cancer is an aggressive disease, with 204,000 cases diagnosed worldwide each year, and is the leading cause of death among all gynecologic tumors.1Siegel R Naishadham D Jemal A Cancer statistics, 2012.CA Cancer J Clin. 2012; 62: 10-29Crossref PubMed Scopus (10424) Google Scholar The late diagnosis, combined with widespread intraperitoneal metastasis and ascites formation, makes it extremely challenging to treat ovarian cancer in which current treatment options are largely ineffective, resulting in a dismal 5-year survival of <25%. Therefore, understanding the molecular mechanisms that mediate ovarian cancer progression is critically important in the search for novel therapeutic approaches. Estrogen-related receptor alpha (ERRα) was among the first orphan members of the nuclear receptor superfamily to be discovered.2Giguère V Yang N Segui P Evans RM Identification of a new class of steroid hormone receptors.Nature. 1988; 331: 91-94Crossref PubMed Scopus (695) Google Scholar Because of its structural similarities with estrogen receptor, initial studies on the possible roles of ERRα focused mainly on the potential cross talk between these two receptors. However, this concept has recently been revisited to reveal estrogen receptor–independent functions that are unique to ERRα in tumor biology. Of particular interest, levels of ERRα, but not those of other family members, are associated with a worse prognosis and have been reported to be elevated in the more-aggressive tumors in ovarian cancer.3Sun P Wei L Denkert C Lichtenegger W Sehouli J The orphan nuclear receptors, estrogen receptor-related receptors: their role as new biomarkers in gynecological cancer.Anticancer Res. 2006; 26: 1699-1706PubMed Google Scholar,4Fujimoto J Alam SM Jahan I Sato E Sakaguchi H Tamaya T Clinical implication of estrogen-related receptor (ERR) expression in ovarian cancers.J Steroid Biochem Mol Biol. 2007; 104: 301-304Crossref PubMed Scopus (42) Google Scholar This opens the possibility that ERRα could directly regulate tumor progression of ovarian cancer cells. However, whether and how ERRα is involved in the process of metastasis remains unknown. Epithelial-to-mesenchymal transition (EMT) is considered a key step in metastasis, including ovarian cancer, which endows carcinoma cells with enhanced migratory and survival abilities that facilitate malignant progression.5Thiery JP Sleeman JP Complex networks orchestrate epithelial-mesenchymal transitions.Nat Rev Mol Cell Biol. 2006; 7: 131-142Crossref PubMed Scopus (3215) Google Scholar,6Huang RY Chung VY Thiery JP Targeting pathways contributing to epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer.Curr Drug Targets. 2012; 13: 1649-1653Crossref PubMed Scopus (64) Google Scholar Recent findings further illustrate a link between EMT and the gain of stem cell properties, and these studies provide a new concept for therapies that target cancer stem cells (CSCs).7Polyak K Weinberg RA Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits.Nat Rev Cancer. 2009; 9: 265-273Crossref PubMed Scopus (2635) Google Scholar Understanding the molecular mechanisms that enable ovarian cancer cell dissemination, in particular characterizing EMT effectors, will yield important insights. Loss or reduction of E-cadherin is a well-established hallmark of EMT, and the zinc finger transcription factors of the Snail/Slug family have been implicated in this repression.8Radisky DC Epithelial-mesenchymal transition.J Cell Sci. 2005; 118: 4325-4326Crossref PubMed Scopus (360) Google Scholar Although downstream effects of Snail/Slug activation are well defined, less is known about primary events that initiate EMT. Moreover, given that directly inhibiting transcription factors is currently infeasible,9Groom CR Hopkins AL Protein kinase drugs–optimism doesn't wait on facts.Drug Discov Today. 2002; 7: 801-802Crossref PubMed Scopus (11) Google Scholar,10Imming P Sinning C Meyer A Drugs, their targets and the nature and number of drug targets.Nat Rev Drug Discov. 2006; 5: 821-834Crossref PubMed Scopus (620) Google Scholar identifying their upstream regulators will also have great therapeutic significance. In this study, we show for the first time that targeted inhibition of ERRα in highly metastatic ovarian cancer cells significantly attenuates EMT, CSC formation, and metastasis in vitro and in vivo. We also provide mechanistic insight suggesting that miR-200s, newly identified targets of ERRα action, is a critical upstream effector of Snail-dependent repression of E-cadherin of ERRα in this process. EMT is an important driver of cancer progression. To assess the functional role of ERRα in EMT, we first transfected OVCAR-3 cells with the wild-type ERRα construct, taking advantage of its low ERRα expression and epithelial morphology, and changes in cell behavior were followed by optical microscopy. Figure 1a shows that OVCAR-3 cells transfected with ERRα lost their cobblestone-like epithelial morphology but were dispersed and assumed a spindle-like fibroblast appearance. These changes are typical of cells with a mesenchymal phenotype. Conversely, we used RNA interference–mediated suppression of ERRα in SKOV-3, which had high ERRα expression and the cells in which were spindle-shaped and exhibited reduced cell–cell contact (Figure 1b). The effectiveness of this small interfering RNA (siRNA) in depleting ERRα expression was confirmed by western blotting (Figure 1b, inset). Knockdown of ERRα could revert the mesenchymal phenotype to an epithelial phenotype (Figure 1b). This was also confirmed by western blot analysis, which showed a decrease of the epithelial cell marker, E-cadherin expression, and an increase of the mesenchymal cell marker, N-cadherin expression, on ERRα overexpression (Figure 1c). Knocking down ERRα also stimulated the induction of E-cadherin and suppressed the expression of N-cadherin (Figure 1c). The use of nonspecific siRNA had no effect. In addition, there was a correlation between ERRα expression and metastatic phenotype in cell lines (Supplementary Figure S1). ERRα was highly expressed in CaOV-3, SKOV-3, and HEYA8 cells, all of which have been shown to frequently metastasize when inoculated into mice.11Buick RN Pullano R Trent JM Comparative properties of five human ovarian adenocarcinoma cell lines.Cancer Res. 1985; 45: 3668-3676PubMed Google Scholar OVCAR-3 and OV-90 cells, which possess less metastatic potential, showed lower ERRα expression.12Langdon SP Isolation and culture of ovarian cancer cell lines.Methods Mol Med. 2004; 88: 133-139PubMed Google Scholar ERRα was absent in human ovarian surface epithelium (OSE), the tissue of origin of epithelial ovarian carcinomas. Together, these data show a critical role of ERRα in the induction of EMT and metastatic phenotypes. Snail and Slug are zinc finger transcription factors that induce EMT and repress E-cadherin gene transcription.13Batlle E Sancho E Francí C Domínguez D Monfar M Baulida J et al.The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells.Nat Cell Biol. 2000; 2: 84-89Crossref PubMed Scopus (2166) Google Scholar,14Cano A Pérez-Moreno MA Rodrigo I Locascio A Blanco MJ del Barrio MG et al.The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression.Nat Cell Biol. 2000; 2: 76-83Crossref PubMed Scopus (2910) Google Scholar,15Bolós V Peinado H Pérez-Moreno MA Fraga MF Esteller M Cano A The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors.J Cell Sci. 2003; 116: 499-511Crossref PubMed Scopus (925) Google Scholar To elucidate the mechanism of ERRα-regulated EMT, we examined changes in expression levels of these transcription factors. Our results showed that overexpression of ERRα was associated with an increase in the expression of Snail but it had no effect on Slug (Figure 2a). To further elucidate the involvement of ERRα in Snail upregulation, ERRα was repressed by the use of siRNA. ERRα-specific siRNA markedly reduced Snail mRNA (Figure 2b). No inhibition was observed with nonspecific siRNA (Figure 2b). Similarly, ERRα siRNA did not affect Slug expression (Figure 2b), suggesting a potent role of Snail in ERRα-mediated EMT regulation. Next, we examined the mechanism by which ERRα increases Snail mRNA expression. This increase could be due to the result of increased synthesis of the transcript and/or stability. To examine whether Snail was activated at the transcriptional level, luciferase reporter containing the 5′ promoter region of Snail was expressed in ERRα-expressing cells. As shown, the expression of ERRα caused a significant increase in the activation of the Snail promoter (Figure 3a). To examine whether ERRα regulates Snail expression at the posttranscriptional level, we performed actinomycin D chase experiments to determine the half-life of Snail mRNA. Figure 3b shows that the half-life of Snail mRNA was dramatically prolonged by ERRα expression. However, in cells that were treated with ERRα siRNA, there was a substantial decrease in the half-life of Snail mRNA (Figure 3c), suggesting that the significant increase in Snail mRNA levels in response to ERRα could be due to the combined effects on both transcription rate and stability. MicroRNAs (miRNAs), a class of 21- to 23-nucleotide-long noncoding RNAs, are emerging as an attractive mechanism to inhibit gene expression posttranscriptionally by either translational blockage or mRNA degradation.16Iorio MV Croce CM MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review.EMBO Mol Med. 2012; 4: 143-159Crossref PubMed Scopus (1302) Google Scholar To identify miRNAs that are regulated by ERRα, we performed an unbiased screen using prediction softwares and the set of miRNAs known to be associated with ovarian cancer progression.17Hu X Macdonald DM Huettner PC Feng Z El Naqa IM Schwarz JK et al.A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer.Gynecol Oncol. 2009; 114: 457-464Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar,18Leskelä S Leandro-García LJ Mendiola M Barriuso J Inglada-Pérez L Muñoz I et al.The miR-200 family controls beta-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients.Endocr Relat Cancer. 2011; 18: 85-95Crossref PubMed Scopus (179) Google Scholar We thus identified the miR-200 family (miR-141, miR-200a, miR-200b, and miR-200c) as Snail regulators. Although previously published data have shown that miR-200 family members can regulate Snail in epiblast differentiation during development,19Gill JG Langer EM Lindsley RC Cai M Murphy TL Kyba M et al.Snail and the microRNA-200 family act in opposition to regulate epithelial-to-mesenchymal transition and germ layer fate restriction in differentiating ESCs.Stem Cells. 2011; 29: 764-776Crossref PubMed Scopus (69) Google Scholar the regulation of Snail by miR-200 family members in tumor cells has never been investigated before. On examining the expression level of miR-141, miR-200a, miR-200b, and miR-200c, we found that the miRNAs are highly expressed in ERRα siRNA–treated cells, whereas nonspecific siRNA–treated cells showed no effect (Figure 4). To assess whether miR-200 was required for ERRα-induced EMT regulation, we used hsa-miR-200a and hsa-miR-200b antagomirs. By inhibiting miR-200a and/or miR-200b, the decreased Snail expression and the reversal of EMT caused by ERRα depletion was significantly inhibited (Figure 5). Because cancer cells that undergo EMT can acquire stem cell properties that promote aggressive metastatic behavior, we determined the presence of CSCs in ERRα knockdown cells. Knockdown of ERRα significantly reduced formation of CSC-enriched spheres (Figure 6a). There was also a significant decrease in the expression of Nanog, Bmi-1, and Oct-4, which are established ovarian CSC markers,20Zhang S Balch C Chan MW Lai HC Matei D Schilder JM et al.Identification and characterization of ovarian cancer-initiating cells from primary human tumors.Cancer Res. 2008; 68: 4311-4320Crossref PubMed Scopus (1037) Google Scholar in ERRα knockdown cells (Figure 6b). We also observed that miR-200a and miR-200b antagomirs had a substantial function in reverting ERRα siRNA–mediated inhibition of sphere formation (Figure 6c). These results reveal a key role of the miR-200 family members in ERRα-mediated EMT regulation and show that miR-200 also has a role in EMT-regulated CSCs.Figure 6Knockdown of ERRα inhibits CSC phenotype. (a) SKOV-3 cells were transfected with nonspecific (NS) siRNA or ERRα siRNA for 72 hours. The number of tumor spheres generated was photographed (left) and counted (right). Results are presented as the mean ± SD and were analyzed using Mann–Whitney U-test. (b) Total RNA was extracted and reverse transcription–polymerase chain reaction was performed using sequence-specific primers to Nanog, Oct-4, and Bmi-1. β-Actin was included as an internal control. The signal intensities were quantified by densitometric analysis and the amount was normalized for the amount of β-actin. Results are presented as the mean ± SD and were analyzed using Mann–Whitney U-test. (c) The number of tumor spheres generated was photographed (left) and counted (right). Bar = 50 µm. Results are presented as the mean ± SD and were analyzed using Kruskal–Wallis test followed by Dunn's test for post hoc analysis. *P < 0.05; **P < 0.01, compared with NS siRNA. Bar = 50 µm. CSC; cancer stem cells; ERRα, estrogen-related receptor alpha; siRNA, small interfering RNA.View Large Image Figure ViewerDownload Hi-res image Download (PPT) To extend these studies in an animal model, we investigated the effect of ERRα silencing on ovarian cancer metastasis. In this in vivo study, luciferase-labeled nonspecific or ERRα siRNA–expressing SKOV-3 cells were orthotopically injected into the ovarian bursa, which emulates the clinical presentation of human patients with ovarian cancer, and subjected to bioluminescence imaging. The results showed that SKOV-3 cells expressing nonspecific siRNA grew as highly aggressive tumors and the tumor cells disseminated to the peritoneum—with visible tumor masses growing on the omentum, mesenteries, and small bowels—and developed ascites, reflecting characteristics commonly displayed by ovarian cancer lesions (Figure 7a). ERRα knockdown led to a marked reduction of the ascites volume compared with the volume in nonspecific siRNA–treated cells (Figure 7b). Similarly, the number and the size of tumor nodules were substantially decreased by treatment with ERRα siRNA than with nonspecific siRNA (Figure 7c), giving further support to the importance of ERRα in ovarian cancer metastasis. As a crucial initial step in cancer metastasis, anti-EMT strategies hold great promise for the treatment of many cancers that currently lack effective therapies. As such, identifying factors that control EMT and the associated malignant features is critical. ERRα overexpression is correlated with poor outcome in ovarian cancer,3Sun P Wei L Denkert C Lichtenegger W Sehouli J The orphan nuclear receptors, estrogen receptor-related receptors: their role as new biomarkers in gynecological cancer.Anticancer Res. 2006; 26: 1699-1706PubMed Google Scholar,4Fujimoto J Alam SM Jahan I Sato E Sakaguchi H Tamaya T Clinical implication of estrogen-related receptor (ERR) expression in ovarian cancers.J Steroid Biochem Mol Biol. 2007; 104: 301-304Crossref PubMed Scopus (42) Google Scholar but the molecular mechanism underlying the aggressive nature of these tumors remains largely unknown. Furthermore, although originally identified as a metabolic regulator, recent evidence suggests that its actions are not confined to metabolic regulation.21Mootha VK Handschin C Arlow D Xie X St Pierre J Sihag S et al.Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.Proc Natl Acad Sci USA. 2004; 101: 6570-6575Crossref PubMed Scopus (552) Google Scholar,22Stein RA Gaillard S McDonnell DP Estrogen-related receptor alpha induces the expression of vascular endothelial growth factor in breast cancer cells.J Steroid Biochem Mol Biol. 2009; 114: 106-112Crossref PubMed Scopus (75) Google Scholar,23Deblois G Hall JA Perry MC Laganière J Ghahremani M Park M et al.Genome-wide identification of direct target genes implicates estrogen-related receptor alpha as a determinant of breast cancer heterogeneity.Cancer Res. 2009; 69: 6149-6157Crossref PubMed Scopus (129) Google Scholar The work presented here is significant in several ways. First, we show for the first time an additional and novel role for ERRα as a critical positive regulator of EMT and subsequent CSC-like properties and an inducer of ovarian cancer metastasis, both in vitro and in vivo. Moreover, we show a new mechanism of action by which ERRα regulates the miR-200 family to modulate the EMT-inducing transcription factor Snail to suppress E-cadherin expression. Given that EMT represents a fundamentally important process in ovarian cancer24Ahmed N Thompson EW Quinn MA Epithelial-mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas: an exception to the norm.J Cell Physiol. 2007; 213: 581-588Crossref PubMed Scopus (188) Google Scholar and that E-cadherin repression is associated with poor outcome in ovarian cancer patients,25Sundfeldt K Cell-cell adhesion in the normal ovary and ovarian tumors of epithelial origin; an exception to the rule.Mol Cell Endocrinol. 2003; 202: 89-96Crossref PubMed Scopus (102) Google Scholar our result that ERRα is involved in the regulation of ovarian tumor progression and metastasis is clinically relevant. There is increasing evidence that members of the Snail family of transcription factors can be differentially regulated.5Thiery JP Sleeman JP Complex networks orchestrate epithelial-mesenchymal transitions.Nat Rev Mol Cell Biol. 2006; 7: 131-142Crossref PubMed Scopus (3215) Google Scholar Thus, despite the many similarities between Snail and Slug, they might play important but distinct roles in cancer progression, and these roles are compatible with current models.26Côme C Magnino F Bibeau F De Santa Barbara P Becker KF Theillet C et al.Snail and slug play distinct roles during breast carcinoma progression.Clin Cancer Res. 2006; 12: 5395-5402Crossref PubMed Scopus (211) Google Scholar,27Shields MA Krantz SB Bentrem DJ Dangi-Garimella S Munshi HG Interplay between ß1-integrin and Rho signaling regulates differential scattering and motility of pancreatic cancer cells by snail and Slug proteins.J Biol Chem. 2012; 287: 6218-6229Crossref PubMed Scopus (52) Google Scholar Moreover, in addition to Snail, other members of the zinc finger transcription factors, including Zeb1, SIP1, E12/E47, and Twist, have also been shown to induce EMT and metastasis through the repression of E-cadherin. Although Snail is implicated in the early step of EMT, Zeb1 and other repressors are responsible for maintenance of the migratory phenotype.28Peinado H Olmeda D Cano A Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?.Nat Rev Cancer. 2007; 7: 415-428Crossref PubMed Scopus (2555) Google Scholar Our data showing that ERRα induces expression of Snail suggest that ERRα may regulate the first and necessary phase of the ovarian cancer dissemination process. These observations follow clinical reports in which primary ovarian tumors are believed to engage the EMT program at the initial dissemination stage.24Ahmed N Thompson EW Quinn MA Epithelial-mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas: an exception to the norm.J Cell Physiol. 2007; 213: 581-588Crossref PubMed Scopus (188) Google Scholar It is also relevant that Snail expression in ovarian carcinomas is associated with a worse prognosis and shows more aggressive biological behavior.29Imai T Horiuchi A Wang C Oka K Ohira S Nikaido T et al.Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells.Am J Pathol. 2003; 163: 1437-1447Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar,30Elloul S Elstrand MB Nesland JM Tropé CG Kvalheim G Goldberg I et al.Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma.Cancer. 2005; 103: 1631-1643Crossref PubMed Scopus (366) Google Scholar,31Blechschmidt K Sassen S Schmalfeldt B Schuster T Höfler H Becker KF The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients.Br J Cancer. 2008; 98: 489-495Crossref PubMed Scopus (116) Google Scholar We show that ERRα affects Snail expression not only through transcriptional regulation of Snail but also through posttranscriptional regulation that targets the 3′ untranslated region of Snail. This dual mechanism of regulation is similar to what has been recently described for insulin-like growth factor (IGF)-I signaling. EWS-Fli1 regulates the IGF-I promoter directly and the expression of IGF-I via miRNAs indirectly.32Cironi L Riggi N Provero P Wolf N Suvà ML Suvà D et al.IGF1 is a common target gene of Ewing's sarcoma fusion proteins in mesenchymal progenitor cells.PLoS ONE. 2008; 3: e2634Crossref PubMed Scopus (88) Google Scholar,33McKinsey EL Parrish JK Irwin AE Niemeyer BF Kern HB Birks DK et al.A novel oncogenic mechanism in Ewing sarcoma involving IGF pathway targeting by EWS/Fli1-regulated microRNAs.Oncogene. 2011; 30: 4910-4920Crossref PubMed Scopus (85) Google Scholar The combined ability of ERRα in increasing Snail transcription and in preventing mRNA degradation indicates that it plays a central role in regulating Snail expression and thus EMT. Here, we also describe a novel oncogenic role of ERRα in regulating miRNAs, although previously published data have shown that ERRα can be regulated by miR-137.34Zhao Y Li Y Lou G Zhao L Xu Z Zhang Y et al.MiR-137 targets estrogen-related receptor alpha and impairs the proliferative and migratory capacity of breast cancer cells.PLoS ONE. 2012; 7: e39102Crossref PubMed Scopus (103) Google Scholar The molecular mechanism by which ERRα might regulate miRNA-200s is not known. However, there are several plausible mechanisms: (i) In its capacity as a transcriptional regulator,35Sladek R Bader JA Giguère V The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene.Mol Cell Biol. 1997; 17: 5400-5409Crossref PubMed Google Scholar,36Tashiro S Wang Z Kotomura N Niwa O Ueda K Kamada N Nuclear proteins binding to the recombination hotspot region of the retinoic acid receptor alpha gene.Leukemia. 1997; 11 Suppl 3: 285-286PubMed Google Scholar ERRα may directly alter miR-200 gene expression. ERRα response elements were found at the promoter regions of the miR-200a/b cluster and miR-200c/141. (ii) Alternatively, ERRα may regulate miRNA biogenesis by downregulating Drosha and Dicer transcriptionally. Transcription is increasingly recognized as an important mechanism of Drosha and Dicer regulation,37Davis BN Hata A Regulation of MicroRNA Biogenesis: A miRiad of mechanisms.Cell Commun Signal. 2009; 7: 18Crossref PubMed Scopus (253) Google Scholar and ERRα-binding sites (TNAGGTCA) within the human Drosha (GenBank accession number NC_000005.9) and Dicer (GenBank accession number NG_016311.1) promoters have been identified. (iii) In addition, although the transcriptional mechanism is well recognized, there is now evidence that nuclear receptors can mediate rapid nongenomic signaling.38Boonyaratanakornkit V Edwards DP Receptor mechanisms mediating non-genomic actions of sex steroids.Semin Reprod Med. 2007; 25: 139-153Crossref PubMed Scopus (130) Google Scholar These issues remain to be elucidated. There is increasing evidence that the induction of EMT in transformed ovarian cancer cells in vitro or in mouse models generates cells with CSC characteristics, suggesting that ovarian epithelial cells can gain CSC characteristics through EMT.39Kang KS Choi YP Gao MQ Kang S Kim BG Lee JH et al.CD24? ovary cancer cells exhibit an invasive mesenchymal phenotype.Biochem Biophys Res Commun. 2013; 432: 333-338Crossref PubMed Scopus (29) Google Scholar,40Latifi A Abubaker K Castrechini N Ward AC Liongue C Dobill F et al.Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile.J Cell Biochem. 2011; 112: 2850-2864Crossref PubMed Scopus (188) Google Scholar Moreover, CSCs derived from ovarian tumors and metastatic ovarian peritoneal effusions express EMT-associated markers.41Visvader JE Lindeman GJ Cancer stem cells in solid tumours: accumulating evidence and unresolved questions.Nat Rev Cancer. 2008; 8: 755-768Crossref PubMed Scopus (2808) Google Scholar Similarly, EMT and CSC markers are frequently associated with ovarian carcinomas that have a propensity to metastasize, thus reinforcing the close relationship of these processes.40Latifi A Abubaker K Castrechini N Ward AC Liongue C Dobill F et al.Cisplatin treatment of primary and metastatic epithelial ovarian carcinomas generates residual cells with mesenchymal stem cell-like profile.J Cell Biochem. 2011; 112: 2850-2864Crossref PubMed Scopus (188) Google Scholar Our studies reveal a role for ERRα in linking EMT and CSCs, which not only expands our understanding of the molecular mechanism but also sheds light on a new therapeutic concept that warrants clinical investigation. This study further confirms an essential role of ERRα in ovarian cancer progression and positions it as an important target for cancer treatment. Because cells of the human OSE generally do not express ERRα (Supplementary Figure S1), its therapeutic targeting may offer a highly selective approach. It is also worth noting that high levels of ERRα are found in various cancers, including ovarian cancer, and high ERRα expression is associated with poor prognosis in breast, colon, and ovarian cancers,42Ariazi EA Clark GM Mertz JE Estrogen-related receptor alpha and estrogen-related receptor gamma associate with unfavorable and favorable biomarkers, respectively, in human breast cancer.Cancer Res. 2002; 62: 6510-6518PubMed Google Scholar,43Suzuki T Miki Y Moriya T Shimada N Ishida T Hirakawa H et al.Estrogen-related receptor alpha in human breast carcinoma as a potent prognostic factor.Cancer Res. 2004; 64: 4670-4676Crossref PubMed Scopus (192) Google Scholar,44Cavall" @default.
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• W2023243872 title "Targeting Estrogen-Related Receptor Alpha Inhibits Epithelial-to-Mesenchymal Transition and Stem Cell Properties of Ovarian Cancer Cells" @default.
• W2023243872 cites W1964673143 @default.
• W2023243872 cites W1965255998 @default.
• W2023243872 cites W1966051785 @default.
• W2023243872 cites W1966620203 @default.
• W2023243872 cites W1985055097 @default.
• W2023243872 cites W1994475534 @default.
• W2023243872 cites W1997014592 @default.
• W2023243872 cites W1999356404 @default.
• W2023243872 cites W2009205364 @default.
• W2023243872 cites W2010441567 @default.
• W2023243872 cites W2014557438 @default.
• W2023243872 cites W2020458598 @default.
• W2023243872 cites W2021880374 @default.
• W2023243872 cites W2023338540 @default.
• W2023243872 cites W2025647419 @default.
• W2023243872 cites W2039313774 @default.
• W2023243872 cites W2039668230 @default.
• W2023243872 cites W2042198997 @default.
• W2023243872 cites W2055570003 @default.
• W2023243872 cites W2056456319 @default.
• W2023243872 cites W2064538929 @default.
• W2023243872 cites W2065552057 @default.
• W2023243872 cites W2068351024 @default.
• W2023243872 cites W2070755882 @default.
• W2023243872 cites W2074747200 @default.
• W2023243872 cites W2084215755 @default.
• W2023243872 cites W2087227011 @default.
• W2023243872 cites W2087367170 @default.
• W2023243872 cites W2093365906 @default.
• W2023243872 cites W2097999618 @default.
• W2023243872 cites W2102681919 @default.
• W2023243872 cites W2111471857 @default.
• W2023243872 cites W2115132010 @default.
• W2023243872 cites W2119554992 @default.
• W2023243872 cites W2122265031 @default.
• W2023243872 cites W2131492087 @default.
• W2023243872 cites W2138784667 @default.
• W2023243872 cites W2140551998 @default.
• W2023243872 cites W2144850478 @default.
• W2023243872 cites W2147283821 @default.
• W2023243872 cites W2155554726 @default.
• W2023243872 cites W2159770815 @default.
• W2023243872 cites W2165901622 @default.
• W2023243872 cites W2165948908 @default.
• W2023243872 cites W2066684013 @default.
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